Drug Interactions between eluxadoline and Etrafon

MONITOR: Coadministration of a phenothiazine with a tricyclic antidepressant (TCA) may result in elevated plasma concentrations of one or both drugs as well as additive adverse effects. Most phenothiazines and TCAs have been found to undergo metabolism by CYP450 2D6, thus competitive inhibition of the enzyme may occur when more than one of these agents are administered. Although these drugs have been used together clinically, the possibility of increased risk of serious adverse effects such as central nervous system depression, tardive dyskinesia, hypotension, and prolongation of the QT interval should be considered, as many of these agents alone can and have produced these effects. In addition, excessive anticholinergic effects may occur in combination use, which can result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of anticholinergic intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures.

MANAGEMENT: Concurrent use of phenothiazines and TCAs should be approached with caution, particularly in the elderly and those with underlying organic brain disease, who tend to be more sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be easily overlooked. Patients should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication (e.g., abdominal pain, fever, heat intolerance, blurred vision, confusion, hallucinations) or cardiovascular toxicity (e.g., dizziness, palpitations, arrhythmias, syncope). Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A dosage reduction in one or both drugs may be necessary if excessive adverse effects develop.

GENERALLY AVOID: The risk of constipation and serious constipation-related adverse reactions may be increased when eluxadoline is used with other drugs that are also associated with this adverse effect. In placebo-controlled studies, constipation occurred in 7% and 8% of patients receiving eluxadoline 75 mg twice daily and 100 mg twice daily, respectively. Approximately 50% of constipation events occurred within the first 2 weeks of treatment, while the majority occurred within the first 3 months. The rates of constipation were similar between eluxadoline and placebo beyond the first 3 months of therapy.

MANAGEMENT: Concomitant use of eluxadoline with other drugs that can cause constipation such as alosetron, anticholinergics, and opioids should generally be avoided. Loperamide may be used occasionally for acute management of severe diarrhea, but chronic use is not recommended, and it should be discontinued immediately if constipation occurs. Eluxadoline should also be discontinued if constipation occurs for more than 4 days.

GENERALLY AVOID: The risk of constipation and serious constipation-related adverse reactions may be increased when eluxadoline is used with other drugs that are also associated with this adverse effect. In placebo-controlled studies, constipation occurred in 7% and 8% of patients receiving eluxadoline 75 mg twice daily and 100 mg twice daily, respectively. Approximately 50% of constipation events occurred within the first 2 weeks of treatment, while the majority occurred within the first 3 months. The rates of constipation were similar between eluxadoline and placebo beyond the first 3 months of therapy.

MANAGEMENT: Concomitant use of eluxadoline with other drugs that can cause constipation such as alosetron, anticholinergics, and opioids should generally be avoided. Loperamide may be used occasionally for acute management of severe diarrhea, but chronic use is not recommended, and it should be discontinued immediately if constipation occurs. Eluxadoline should also be discontinued if constipation occurs for more than 4 days.